Achira AA, et al., J Hum Endocrinol 2019, 3: 014 DOI: 10.24966/HE-9640/100014 HSOA Journal of Human

Case Report

presumptive clinical diagnosis based on physical, radiographic, and Primary histopathological findings is sufficient for initiating therapy for adre- Due to Tuberculous Adrenalitis nal TB. in a Patient without Active Pul- Abbreviations TB - Tuberculosis monary Tuberculosis ACTH - Adrenocorticotropic Hormone Ali A Achira1*, Dania Abushanab1, Hussein Elbadawi1, Sorabh CT - Computed Tomography Dhar2 and Wael Taha1 PCR - Polymerase Chain Reaction 1Department of Endocrinology and Metabolism, Wayne State University, Introduction Michigan, USA Tuberculous adrenalitis is an extremely rare cause of Addison dis- 2Department of Infectious Disease, Wayne State University, Michigan, USA ease [1]. Even with current effective therapies, adrenal TB, usually caused by haematogenous spread of pulmonary TB, continues to be a cause of primary adrenal insufficiency in developing countries [2]. Abstract Adrenal TB is seen in 6 % of patients with active pulmonary TB [3]. Objective Clinical manifestations of Addison disease are seen in only 12 % of patients who have active adrenal TB and occur when 90 % of adrenal Our objective is to identify diagnostic clues indicative of primary tissue is destroyed by the infection [3]. adrenal insufficiency secondary to Tuberculosis (TB) in a patient with negative Mycobacterium TB PCR analysis Case Report Methods A 38 year old African man from Uganda, who immigrated to the We described a case report, and we performed all the possible USA 3 years prior to his sickness, presented a tour hospital with nau- investigations to confirm the diagnosis. sea, vomiting and weakness. He reported having decreased appetite Results with unintentional weight loss of 20 pounds in the 4 months prior to presentation. Examination revealed low blood pressure (94/65 A 38 year old man was admitted with signs and symptoms of adrenal insufficiency. Morning level was low, with very high mmHg), orthostatic hypotension, and skin hyperpigmentation along Adrenocorticotropic Hormone (ACTH). He failed the cosyntropin the creases of the palms and proximal and distal interphalangeal joints stimulation test. Tuberculin skin test (Purified Protein Derivate-PPD) (Figure 1). and QuantiFERON test were positive. CT scans of the abdomen and pelvis showed diffuse, enlarged adrenal glands with a 5.8 cm mass in the left , the biopsy of which showed chronic inflammation with Langerhans giant cells. However, Mycobacteri- al stains, cultures, and Polymerase Chain Reaction (PCR) results were negative. Primary adrenal insufficiency secondary to TB was the presumptive diagnosis, and the patient was started on adrenal replacement therapy and anti-tubercular therapy. Conclusion This case highlights the fact that negative Mycobacterium cul- ture and TB PCR results may not rule out tuberculous adrenalitis. A

*Corresponding author: Ali A Achira, Department of Endocrinology and Me- tabolism, Wayne State University, Michigan, USA, Tel: +1 3137451464; E-mail: Figure 1: Hyperpigmentation along the creases of the palms and proximal and distal [email protected] interphalangeal joints. Citation: Achira AA, Abushanab D, Elbadawi H, Dhar S and Taha W (2019) Primary Adrenal Insufficiency Due to Tuberculous Adrenalitis in a Patient with- Laboratory tests indicated low serum sodium (125 mEq/L [nor- out Active Pulmonary Tuberculosis. J Hum Endocrinol 4: 014. mal, 136-142 mEq/L]), high serum potassium (6.2 mEq/L [normal, Received: June 28, 2019; Accepted: July 19, 2019; Published: July 26, 2019 3.5-5.0 mEq/L]), high serum creatinine (1.5 mg/dL [normal, 0.6-1.2 mg/dL]), and low serum 8 AM cortisol (2 µg/dL [normal, 5-25 µg/ Copyright: © 2019 Achira AA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits un- dL]). Results of the cosyntropin stimulation test were consistent with restricted use, distribution, and reproduction in any medium, provided the original primary adrenal insufficiency, because random cortisol level was 1.8 author and source are credited. µg/dL (normal, 5-25 µg/dL) before the test, and 1.9 µg/dL 60 minutes Citation: Achira AA, Abushanab D, Elbadawi H, Dhar S, Taha W (2019) Primary Adrenal Insufficiency Due to Tuberculous Adrenalitis in a Patient without Active Pulmonary Tuberculosis. J Hum Endocrinol 4: 014.

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after the test (normal, post 60 minutecortisol level >18 µg/dL). His ACTH level at 8 AM was 655 pg/mL (normal, <120 pg/mL), con- firming primary adrenal insufficiency. The patient was started on intravenous fluid replacement, hydrocortisone, and fludrocortisone. Marked clinical improvement was observed within 24 hours of start- ing treatment. Further investigation of adrenal insufficiency revealed a positive PPD test (22 × 28 mm induration), and the result of the TB QuantiF- ERON Gold test was high (>10 IU/mL [FDA cut point for a positive result is >0.34 IU/mL]). Lab tests summarized in the table below:

Figure 2B: CT scan of the abdomen showing asymmetric, bilateral enlargement of Patient’s results Normal range Comment the adrenal glands. Serum sodium 125 mEq/L 136-142 mEq/L Low Serum potassium 6.2 mEq/L 3.5-5.0 mEq/L High Biopsy of the mass showed chronic inflammation with Langer- Serum creatinine 1.5 mg/dL 0.6-1.2 mg/dL High hans giant cells (Figure 3) and necrotic tissue. These results were Serum 8 AM cortisol 2 µg/dL 5-25 µg/dL Low histologically consistent with a granulomatous process (Tuberculous Cosyntropin stimu- adrenalitis). No normal adrenal tissue could be identified. There was lation test no evidence of malignancy. Fungal cultures and stains of the tissue bi- Random cortisol level before cosyn- 1.8 µg/dL Normal, 5-25 µg/dL Low opsy were negative. Bacterial cultures and gram stains were negative. tropin Mycobacterial cultures and stains for acid-fast bacilli were negative Serum cortisol 60 Normal, post 60 after >8 weeks. Mycobacterium TB PCR analysis of tissue biopsy was min after cosyn- 1.9 µg/dL Low minute >18 µg/dL negative. Urine cultures for Mycobacterium were negative. tropin ACTH 655 pg/mL <120 pg/mL High 22 × 28 mm PPD test Positive induration FDA cut point for TB QuantiFERON >10 IU/mL High a positive result is Gold >0.34 IU/mL

Chest radiography was normal. High-resolution CT chest scans showed a 5 mm nodule in the right upper lobe with mild right hilar adenopathy (Gohn’s complex), suggesting evidence of old pulmonary TB exposure. Three mycobacterial sputum stains were negative for acid-fast bacilli. CT scans of the abdomen and pelvis showed diffuse, enlarged adrenal glands with a 5.8 cm mildly enhancing mass in the left adrenal gland (Figures 2A and 2B). Figure 3: Biopsy of the left adrenal gland showing chronic inflammation with Lang- erhans giant cells.

Additional evaluation to determine alternative causes of adrenal insufficiency was conducted, including tests for: HIV, syphilis, fungal antibodies against Aspergillus, Blastomyces, Coccidiodes, Candida, and Histoplasma and fungal cultures of the adrenal gland and adrenal antibodies. All of these tests were negative and did not implicate an alternate cause. The patient was started on isoniazid, rifampin, eth- ambutol and pyrazinamide, in addition to adrenal insufficiency treat- ment. Treatment for TB Adrenalitis is same duration as for pulmonary TB with 4 drug therapy (Isoniazid, rifampin, ethambutol and pyra- zinamide) for 8 weeks (Intensive phase) followed by 2 drug therapy (Isoniazid and rifampin) for 18 weeks (Continuation phase).

Figure 2A: CT scan of the abdomen showing a 5.8 cm mildly enhancing mass in the Acute symptoms improved after starting hormone replacement left adrenal gland. therapy. However it is difficult to ascertain if the patient has respond- ed to TB treatment or hormone replacement therapy as it could be the

Volume 3 • Issue 1 • 100014 J Hum Endocrinol ISSN: 2572-9640, Open Access Journal DOI: 10.24966/HE-9640/100014 Citation: Achira AA, Abushanab D, Elbadawi H, Dhar S, Taha W (2019) Primary Adrenal Insufficiency Due to Tuberculous Adrenalitis in a Patient without Active Pulmonary Tuberculosis. J Hum Endocrinol 4: 014.

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result of both. It is difficult to tease out which resulted in improvement Conclusion and is likely due to the treatment of both the hormonal abnormalities as well as the infection. The immediate improvement seen was likely This case demonstrates that failure to isolate M. tuberculosis from from the steroid replacement and less from the TB medications. patients suspected of pulmonary or extra-pulmonary (adrenal) TB does not exclude a diagnosis of TB. A presumptive clinical diagnosis Monitoring plan is to get repeat CXR to monitor the lung findings based on epidemiologic exposure, positive tuberculin skin tests, phys- at 2 months of treatment and at the end of treatment visit. Plan also to ical findings, radiographic findings, sputum/secretions/fluid analyses, repeat imaging of the abdomen at 2 months and the end of the treat- and/or histopathology is sufficient for initiating therapy for tubercu- ment to assess for changes in the enlarged adrenal gland. lous adrenalitis. Recovery of adrenal function, although atypical, is possible after appropriate anti-TB therapy. Discussion Acknowledgment TB can affect many endocrine glands, including the hypothala- mus, pituitary, and thyroid glands, but the most commonly involved Dr. Abdullah Mallisho had assisted in editing this case report. endocrine organ is the adrenal gland [4]. Most cases of adrenal TB are References found 10-15 years after the initial infection; hence, tuberculous Addi- son disease has a relatively late onset and delayed diagnosis [4,5]. 1. Oelkers W (1996) Adrenal insufficiency. N Engl J Med 335: 1206-1212. This patient had extra-pulmonary TB involving the adrenal 2. Keleştimur F, Ozbakir O, Sağlam A, Oztürk F, Yücesoy M (1993) Acute glands, resulting in adrenal insufficiency. However, it is unknown adrenocortical failure due to tuberculosis. J Endocrinol Invest 16: 281-284. when he was first exposed to TB. TB infection frequently begins in 3. Vita JA, Silverberg SJ, Goland RS, Austin JH, Knowlton AI (1985) Clini- the lungs and may disseminate via the haematogenous route to ex- cal clues to the cause of Addison’s disease. Am J Med 78: 461-456. tra-pulmonary sites, especially to the organs with high blood flow, 4. Llewelyn M, Adler M, Steer K, Pasvol G (1999) Acute adrenal insufficien- such as the spleen, liver, bone marrow, kidneys, and adrenal glands cy precipitated by isolated involvement of the adrenal gland by tuberculo- [6]. Dissemination of M. tuberculosis may occur at the time of prima- sis. J Infect 39: 244-245. ry pulmonary infection or later, due to a re-infection or reactivation of 5. Lam KY, Lo CY (2001) A critical examination of adrenal tuberculosis and a previous infection [6]. Characteristic granulomas may result from a 28-year autopsy experience of active tuberculosis. Clin Endocrinol (Oxf) acute lymphohematogenous dissemination (soft or exudative granulo- 54: 633-639. ma, frequently having acid-fast bacilli) or discharge of bacilli into the 6. Guttman PH (1930) Addison’s disease: A staristical analysis of 566 cases microscopic blood vessels within the caseous lesions (Hard granulo- and a study of the pathology. Arch Pathol 10: 742-935. ma, frequently having no acid-fast bacilli) [7]. In the present case, no 7. Sharma SK, Mohan A (2004) Extrapulmonary tuberculosis. Indian J Med acid-fast bacilli were detected in granulomas from the adrenal biopsy. Res 120: 316-353. Enlargement of both adrenal glands can occur in most (90 %) patients 8. Doppman JL, Gill JR, Nienhuis AW, Earll JM, Long JA (1982) CT findings with tuberculous adrenal insufficiency [8-10]. Imaging findings may in Addison’s disease. J Comput Assist Tomogr 6: 757-761. vary with the stage and activity of the inflammatory process. In an early tuberculous adrenalitis, bilateral adrenal enlargement is typical, 9. Guo YK, Yang ZG, Li Y, Ma ES, Deng YP, et al. (2007) Addison’s disease due to adrenal tuberculosis: Contrast-enhanced CT features and clinical as in the present case, which can include a central necrotic area of duration correlation. Eur J Radiol 62: 126-131. low attenuation and a peripheral enhancing rim. At the late or healing stage, an enlargement of tuberculous adrenal glands may partially or 10. Wang YX, Chen CR, He GX, Tang AR (1998) CT findings of adrenal glands in patients with tuberculous Addison’s disease. J Belge Radiol 81: completely resolve, with or without calcification or atrophy [11-13]. 226-228. No adrenal calcification was observed in the present patient. 11. Kawashima A, Sandler CM, Fishman EK, Charnsangavej C, Yasumori K, TB cannot be excluded in some patients if Acid Fast Bacilli (AFB) et al. (1998) Spectrum of CT findings in nonmalignant disease of the adre- smear results are negative. Thus, a clinician’s judgment should be nal gland. Radiographics 18: 393-412. used regarding the initiation of empiric TB therapy, while awaiting 12. Yang ZG, Guo YK, Li Y, Min PQ, Yu JQ, et al. (2006) Differentiation culture results [14-16]. between tuberculosis and primary tumors in the adrenal gland: evaluation with contrast-enhanced CT. Eur Radiol 16: 2031-2036. In the USA, approximately 17 % of reported new cases of pul- 13. Guo YK, Yang ZG, Li Y, Deng YP, Ma ES, et al. (2007) Uncommon adre- monary TB have negative cultures. Failure to isolate M. tuberculosis nal masses: CT and MRI features with histopathologic correlation. Eur J from appropriately collected patient specimens suspected of pulmo- Radiol 62: 359-370. nary TB (on clinical or radiographic grounds) does not exclude a 14. Sharma SK, Tandan SM, Saha PK, Gupta N, Kochupillai N, et al. (2005) diagnosis of TB. It is unclear whether anti tuberculous therapy can Reversal of subclinical adrenal insufficiency through antituberculosis rescue the adrenal function in these patients. Some studies show that treatment in TB patients: a longitudinal follow up. Indian J Med Res 122: the recovery of adrenal function can occur in patients treated for TB 127-131. [14-16], but a lack of adrenal recovery 2-5 years after therapy has 15. Bhatia E, Jain SK, Gupta RK, Pandey R (1998) Tuberculous Addison’s also been observed [17]. In our patient, TB treatment was initiated, disease: lack of normalization of adrenocortical function after anti-tuber- in addition to hydrocortisone and fludrocortisone. Adrenal function culous chemotherapy. Clin Endocrinol (Oxf) 48: 355-359. will be monitored during the course of therapy. However, recovery is 16. Penrice J, Nussey SS (1992) Recovery of adrenocortical function follow- less likely, as the biopsy failed to identify any normal adrenal tissue, ing treatment of tuberculous Addison’s disease. Postgrad Med J 68: 204- 205. indicating that >90 % of adrenal tissue had been destroyed by the infection. TB is not expected to spread as it has been treated. No other 17. Keven K, Uysal AR, Erdogan G (1998) Adrenal function during tubercu- damage to other organs anticipated following treatment. lous infection and effects of antituberculosis treatment on endogenous and exogenous steroids. Int J Tuberc Lung Dis 2: 419-424.

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